Mycology, pathogenesis, and epidemiology of blastomycosis

INTRODUCTION — Blastomycosis is a systemic pyogranulomatous infection primarily involving the lungs, which can be asymptomatic or can manifest as acute or chronic pneumonia. Hematogenous dissemination frequently occurs; extrapulmonary disease of the skin, bones, and genitourinary system is common, but almost any organ can be infected. Infection arises after inhalation of the conidia of Blastomyces dermatitidis or Blastomyces gilchristii.

Blastomyces is a member of the family Ajellomycetaceae and order Onygenales. Fungal nomenclature has been changing based on multilocus phylogenetic analyses and sequencing, and Blastomyces helicus, Blastomyces parvus, Blastomyces silverae, and Blastomyces percursus have been placed in the genus Blastomyces rather than the genus Emmonsia [1,2]. B. helicus has been associated with disease in a small number of humans and domestic animals [3].

The basic mycology, pathogenesis, and epidemiology of blastomycosis will be reviewed here. The clinical manifestations and treatment of blastomycosis are discussed separately. (See "Clinical manifestations and diagnosis of blastomycosis" and "Treatment of blastomycosis".)

MYCOLOGY — Blastomyces is a member of the family Ajellomycetaceae and order Onygenales. Phylogenetic analysis of 78 clinical and environmental isolates of B. dermatitidis from different geographic regions has revealed two distinct species of the fungus, B. dermatitidis and B. gilchristii [4]. In addition, fungal nomenclature has been changing based on multilocus phylogenetic analyses and sequencing, and B. helicus, B. parvus, B. silverae, and B. percursus have now been placed in the genus Blastomyces rather than the genus Emmonsia [1,2]. B. helicus has been associated with disease in a small number of humans and domestic animals [3]. (See 'Epidemiology' below.)

●B. dermatitidis and B. gilchristii – The natural habitat of 169 strains of organisms collected from various geographic areas were examined with 25 microsatellite loci for phylogeographic analysis [5]. B. gilchristii strains were found only in isolates from Canada and some northern states in the US, while B. dermatitidis were from those same locations, plus along the Mississippi River drainage system and in southeastern states. Both were closely linked to freshwater drainage systems, and the diversity was speculated to have begun with receding glaciers covering much of North America in the Pleistocene epoch [5]. (See 'Epidemiology' below.)

B. dermatitidis and B. gilchristii appear to cause similar clinical illness. Clinical laboratories do not differentiate between these two species and simply call them B. dermatitidis. Thus, the organism will be referred to as B. dermatitidis hereafter.

B. dermatitidis refers to both the sexual and asexual stage of the organism. Previously, Ajellomyces dermatitidis was the name of the sexual stage of the organism, and B. dermatitidis was the name for the asexual state of the organism. Production of a sexual spore requires fusion of the nucleus of a positive type with a negative, the so-called heterothallic property; both mating types are equally capable of causing infection [6].

Two serotypes of B. dermatitidis have been identified based upon the presence or absence of the A antigen. In a study of 102 isolates predominantly from North America, all of the North American isolates reacted with anti-A antibody, while 11 of 12 isolates from Africa failed to react [7]. Serologic differences in B. dermatitidis isolates from different geographic location in the United States and Africa have been detected using an enzyme-linked immunoassay, indicating that different genotypic groups exist [8-10]. The expression of clinical disease differs between African strains and others. One report of two different serotypes of B. dermatitidis from Africa showed serotype 2 strains lacked the coding sequence for the surface protein adhesin WI-1 in their genome, which may contribute to the observed differences in strain behavior [11].

B. dermatitidis exhibits thermal dimorphism, growing as the mycelial phase at room temperature and as the yeast phase at 37ºC. Primary isolation is most dependable for the mycelial phase; colonies usually appear after one to three weeks of incubation at 30ºC. The mycelial colonies initially grow as a white mold that slowly turns light brown. The branching hyphae are 2 to 3 microns in diameter and have right angle conidiophores with a single round or oval terminal conidium. Early identification of mycelial cultures is possible using commercial test kits that identify fungal specific exoantigens or by chemiluminescent deoxyribonucleic acid (DNA) probes that recognize unique ribosomal ribonucleic acid (rRNA) sequences [12,13].

B. dermatitidis changes into the yeast phase at 37°C. This dimorphism appears to result from a hybrid histidine kinase, which senses host signals and causes the mycelial to yeast shift of B. dermatitidis [14]. The wrinkled yeast colonies are cream or tan in color.

Yeast cells, usually 8 to 15 microns in diameter, have a thick refractile cell wall (picture 1) and are multinucleate (picture 2). Reproduction is by a single broad-based bud (picture 3); the daughter cell is often as large as the mother cell before detachment.

●B. helicus – B. helicus, which is morphologically distinct from B. dermatitidis and B. gilchristii, was formerly identified as Emmonsia helicus. The organisms are pleomorphic, variable-sized yeast cells that can have single or multiple buds, sometimes forming a chain [3]. The mycelial phase growth produces no conidia and has tightly coiled helical hyphae [3].

PATHOGENESIS — Blastomycosis infection begins with the inhalation of the conidia of B. dermatitidis. Following inhalation, conidia can undergo nonspecific phagocytosis and killing mediated by polymorphonuclear leukocytes (PMN), monocytes, and alveolar macrophages. In contrast, the yeast forms of the organism are more resistant to phagocytosis and killing. As an example, PMN can ingest conidia and kill approximately 50 percent, compared with 20 percent killing of yeast, which are too large for ingestion and are killed by PMN attachment and degranulation [15]. Conidia, the infectious stage, are converted to the yeast phase in tissue. This conversion results in a survival advantage and probably contributes to infection by B. dermatitidis.

Virulence factors — Most dimorphic fungi grow as nonpathogenic molds in the environment and convert to pathogenic yeast in the host, suggesting that virulence factors are important for this phase change [16]. The cell wall of the yeast form of B. dermatitidis is the most well-studied virulence factor for the organism. The cell wall is quite thick, which contributes to its resistance to phagocytosis. The lipid and phospholipid content of the yeast cell wall have also been associated with virulence [17,18].

Conversion of B. dermatitidis to the yeast form induces the expression of an essential virulence factor, BAD-1 (formerly WI-1), a 120 kd glycoprotein adhesion and immune modulator of B. dermatitidis [16,19]. BAD-1 is expressed on the cell surface and is released into the extracellular matrix [16,20]. Yeast phase-specific gene expression of BAD-1 is transcriptionally regulated and its promoter shares homology with that of the yeast phase-specific gene of Histoplasma capsulatum [21]. BAD-1 functions as an adhesin that can bind to CR3 and CD14 of human macrophages [22]. It contains a cysteine-rich domain at its carboxy terminal end that is similar to epidermal growth factor (EGF) and may mediate binding to extracellular matrix [23]. The C terminal EGF-like domain is required for BAD-1 localization to yeast surfaces during cell wall biogenesis.

One group of investigators utilized a recombinant strain of B. dermatitidis that lacked BAD-1 (WI-1) and was not pathogenic in animals as a live-attenuated vaccine in mice; administration of the vaccine strain induced a cellular immune response by CD4+ and CD8+ type 1 (T1) cells and protected animals against lethal experimental pulmonary infection [24,25]. Although interleukin (IL)-12 was absolutely required for cellular immunity, a differential dependency was noted in that CD4+ T cells required IL-12 whereas CD8+ T cells were less dependent on this cytokine. However, once CD4+ and CD8+ T cells have acquired a protective T1 phenotype, the presence of IL-12 was not necessary for maintenance of protective memory [24].

The results of these studies indicate that developing a vaccine to prevent disease in humans is possible. Potential candidates for such a vaccine might include those at high risk of developing blastomycosis such as woodsmen, veterinarians, and immunocompromised hosts living in endemic areas. Although these animal studies are promising, this vaccine strain has not yet been tested in humans.

Genotype — In one study, microsatellite genotyping was performed on 227 isolates of B. dermatitidis from Wisconsin collected over a 10-year period, and the genotype (group 1 or 2) was correlated to clinical phenotype [26]. On univariate analysis, genotype group 1 isolates were more likely to be associated with pulmonary-only infections and constitutional symptoms such as fever, whereas genotype group 2 isolates were more likely to be associated with disseminated disease, older age, and the presence of comorbidities. However, on multivariate analysis, only time from disease onset to diagnosis of >1 month, older age, and cigarette smoking were found to be independently associated with group 2 genotype infections. It is possible that the associations observed on univariate analysis were not detected on multivariate analysis due to inadequate sample size. Additional research needs to be done to determine whether an association exists between genotype and clinical manifestations.

Host defense — The major acquired host defense against B. dermatitidis is cellular immunity, which is mediated by antigen-specific T lymphocytes and lymphokine-activated macrophages. Subcutaneous injections of live or killed B. dermatitidis in mice induces cellular immunity [27], and resistance to infection parallels the development of the cellular immune response, including delayed-type hypersensitivity and proliferative responses in splenocytes and lymph node cells [28,29]. The development of antigen-induced lymphocyte proliferation has been documented clinically with a variety of Blastomyces antigens [30-32].

In contrast with cellular immunity, specific antibody against B. dermatitidis does not appear to confer resistance to or hasten recovery from clinical infection [29].

EPIDEMIOLOGY — Our knowledge of the epidemiology of blastomycosis remains incomplete because of the lack of well-characterized antigens for skin testing or for seroepidemiologic studies. Current information on the epidemiology of blastomycosis is based upon clinical reports of sporadic cases in humans and dogs and the study of point source outbreaks of disease [33].

B. dermatitidis and B. gilchristii

●Geographic distribution – Most cases of blastomycosis have been reported in North America. Endemic areas include the southeastern and south-central states bordering the Mississippi and Ohio River basins, the midwestern states and Canadian provinces bordering the Great Lakes, and a small area in New York and Canada along the St. Lawrence River and the Nelson River. There have been more reports of sporadic blastomycosis in Ontario, Manitoba, New York, and Wisconsin in recent years [34-36]. Outside of North America, blastomycosis has been reported most frequently in Africa, with occasional cases identified in Mexico, Central and South America, India, and the Middle East.

Phylogenetic analysis of 78 clinical and environmental isolates of B. dermatitidis from different geographic regions has revealed two distinct species of the fungus, B. dermatitidis and B. gilchristii [4]. B. gilchristii was isolated from two North American locations known to be hyperendemic for blastomycosis: the Kenora region of Ontario and the Eagle River region of Wisconsin. There is speculation as to whether the high rates of infection in these areas might be due to B. gilchristii being a more pathogenic species or whether favorable environmental factors allowed emergence of this species. (See 'Mycology' above.)

Outbreaks or epidemics of blastomycosis have been reported and have often been associated with waterways [33,34]. An outbreak of blastomycosis occurred in Indianapolis, Indiana, between 2005 and 2008; 34 cases were diagnosed during this time and coincided with major highway projects in the same region [37]. The peak incidence was 1.15 cases per 100,000 population in 2006, compared with 0.12 per 100,000 population in 2003.

The ecology of blastomycosis has not been completely defined because of the difficulty in isolating the organism in nature. However, the environmental isolation of B. dermatitidis in association with two outbreaks of disease has been instrumental in clarifying the ecologic niche of the organism [38,39]. In both studies, Blastomyces was isolated from soil containing decaying vegetation or from decomposed wood. The recent rainfall and the proximity to water noted in both outbreaks support the concept that humidity is important in promoting growth of the organism. A variety of wood by-products and animal waste substrates, in combination, support the growth of B. dermatitidis [40].

Thus, B. dermatitidis probably grows as microfoci in the warm, moist soil of wooded areas rich in organic debris. The conditions that support growth of Blastomyces in these microfoci probably exist for only a short time. When a sporadic case or outbreak is identified, a possible explanation for the inability to isolate the organism in the environment is that the conditions promoting growth may no longer exist at the site of exposure.

●Characteristics associated with infection – A large outbreak of 55 cases of blastomycosis occurred in Marathon County in North Central Wisconsin in 2009 and 2010 [41]. Among patients in the outbreak, 65 percent were male and 45 percent were of Hmong ethnicity, the predominant Asian group in the affected county. The overall incidence of blastomycosis increased significantly since 2005 (average 11 percent increase per year), and the incidence was significantly higher among Asian than non-Asian populations (2010 incidence: 168 versus 13 per 100,000 population). Since 2005, the incidence of blastomycosis increased more than 500 percent among the Hmong population in this region. When cases that were clustered in households and neighborhoods were compared with controls from the same households and neighborhoods that did not have blastomycosis, Hmong ethnicity and having a chronic medical condition were independently associated with development of blastomycosis. Exposures usually associated with increased risk for blastomycosis were not seen in the Asian cases. These observations raise the question as to whether there is a genetic predisposition leading to infection with B. dermatitidis among the Hmong.

Despite early studies of endemic cases, which indicated that middle-aged men with outdoor occupations were at greatest risk for blastomycosis, review of most reported outbreaks indicates no sex, age, occupation, or seasonal predilection for blastomycosis. Exposure to soil, whether related to work or recreation, appears to be the common factor associated with both endemic and epidemic disease.

A review was performed using the State Inpatient Database from the United States Agency for Healthcare Research and Quality (AHRQ) from 46 states [42]. Men accounted for 64 percent of cases, and the median age was 53. The incidence of hospitalization due to infection with this fungus was similar to previous reports from endemic areas in states within the Mississippi and Ohio River valleys. Illinois and Kentucky had the highest increase in incidence between 2001 and 2011, whereas Wisconsin had the highest age-adjusted hospitalization incidence of 2.9 hospitalizations per 100,000 patient-years.

Not all patients diagnosed with blastomycosis are hospitalized, although reported hospitalization rates range from 57 to 70 percent [35,41,42]. However, these numbers are thought to be falsely elevated due to detection of the more severe cases by surveillance programs.

An analysis of 477 patients from one health system revealed racial differences in hospitalization from blastomycosis, with a greater frequency, despite a younger age, in Asian, African American, and American Indian or Alaska Native populations compared with non-Hispanic White persons. Non-Hispanic White individuals were more likely to have had B. dermatitidis isolated than the other groups, who were more likely to have had isolation of B. gilchristii [43].

B. helicus — B. helicus has been reported in a small number of infections in humans and domestic animals in western Canada and western United States [3]. Six of the seven humans with available clinical data had immunocompromising conditions, including human immunodeficiency virus (HIV)/ acquired immunodeficiency syndrome (AIDS), liver transplantation, lupus erythematosus, chronic leukemia with use of corticosteroids, and diabetes mellitus with concurrent alcoholism [3]. Blood cultures and cerebrospinal fluid and bronchoalveolar fluid cultures yielded the organism. Only two of the seven patients survived.

SUMMARY

●Blastomycosis is a systemic pyogranulomatous infection primarily involving the lungs, which can be asymptomatic or can manifest as acute or chronic pneumonia. Hematogenous dissemination frequently occurs; extrapulmonary disease of the skin, bones, and genitourinary system is common, but almost any organ can be infected. (See 'Introduction' above.)

●Phylogenetic analysis has revealed two distinct species of the fungus, Blastomyces dermatitidis and Blastomyces gilchristii. Clinically, the organisms appear to cause similar clinical illness, are not differentiated by clinical laboratories, and will be referred to as B. dermatitidis hereafter. In addition, fungal nomenclature has been changing based on multilocus phylogenetic analyses and sequencing, and Blastomyces helicus, Blastomyces parvus, Blastomyces silverae, and Blastomyces percursus have now been placed in the genus Blastomyces rather than the genus Emmonsia. B. helicus has been associated with disease in a small number of humans and domestic animals. (See 'Mycology' above.)

●Blastomyces exhibits thermal dimorphism, growing as the mycelial phase at room temperature and as the yeast phase at 37°C. Yeast cells, usually 8 to 15 microns in diameter, have a thick refractile cell wall (picture 1) and are multinucleate (picture 2). Reproduction is by a single broad-based bud (picture 3); the daughter cell is often as large as the mother cell before detachment. (See 'Mycology' above.)

●Following inhalation, conidia can undergo nonspecific phagocytosis and killing mediated by polymorphonuclear leukocytes (PMN), monocytes, and alveolar macrophages. In contrast, the yeast forms of the organism are more resistant to phagocytosis and killing. As an example, PMN can ingest conidia and kill approximately 50 percent compared with 20 percent killing of yeast, which are too large for ingestion and are killed by PMN attachment and degranulation. (See 'Pathogenesis' above.)

●Most dimorphic fungi grow as nonpathogenic molds in the environment and convert to pathogenic yeast in the host, suggesting that virulence factors are important for this phase change. The cell wall of the yeast form of B. dermatitidis is the most well-studied virulence factor for the organism. The cell wall is quite thick, which contributes to its resistance to phagocytosis. The lipid and phospholipid content of the yeast cell wall have also been associated with virulence. (See 'Virulence factors' above.)

●Conversion of B. dermatitidis to the yeast form induces the expression of an essential virulence factor, BAD-1 (formerly WI-1), a 120 kd glycoprotein adhesion and immune modulator of B. dermatitidis. (See 'Virulence factors' above.)

●The major acquired host defense against B. dermatitidis is cellular immunity, which is mediated by antigen-specific T lymphocytes and lymphokine-activated macrophages. (See 'Host defense' above.)

●Most cases of blastomycosis have been reported in North America. Endemic areas include the southeastern and south-central states bordering the Mississippi and Ohio River basins, the midwestern states and Canadian provinces bordering the Great Lakes, and a small area in New York and Canada along the St. Lawrence River. Outside of North America, blastomycosis has been reported most frequently in Africa with occasional cases identified in Mexico, Central and South America, India, and the Middle East. (See 'B. dermatitidis and B. gilchristii' above.)

●Outbreaks or epidemics of blastomycosis have been reported and have often been associated with waterways. Exposure to soil, whether related to work or recreation, appears to be the common factor associated with both endemic and epidemic disease. (See 'B. dermatitidis and B. gilchristii' above.)

●B. helicus has been isolated in the western United States and western Canada. In humans, disease has been seen primarily in patients with immunocompromising conditions. (See 'B. helicus' above.)